ABSTRACT Aims Gestational diabetes (GDM) is the strongest known risk factor for maternal type 2 diabetes. However, little is known about type 2 diabetes risk in women with normal glucose challenge test (GCT) results during pregnancy. We investigated the association between GCT results in the normal range and type 2 diabetes risk, both overall and across pre‐pregnancy BMI categories. Materials and Methods This retrospective cohort study identified pregnant women aged 20–50 who had normal (< 140 mg/dL) GCT results between 2004 and 2022. Follow‐up for type 2 diabetes extended from the date of the last documented GCT until 31 September 2024. Survival analyses examine GCT and combine BMI‐GCT exposures. Results Among 249 190 eligible women (mean age 32.7 years), 1354 developed type 2 diabetes during a median follow‐up of 7 years. GCT results within the normal range were associated with the risk of type 2 diabetes, in a graded manner, without a clear threshold. Compared to women with normal pre‐pregnancy BMI and GCT of 70–89 mg/dL, women with a GCT of 130–140 mg/dL had adjusted hazard ratios for type 2 diabetes ranging from 14.7 (95% CI: 6.2–33.3) among women with normal BMI to 145 (95% CI: 67.7–309) among women with obesity. Conclusions Pre‐pregnancy BMI and GCT values within the normal range can be used for further type 2 diabetes risk stratification, ranging from minimal risk among women with a GCT < 90 mg/dL and normal weight to substantially increased risk among women with pre‐pregnancy overweight or obesity.
AIMS:The long-term cardiometabolic effects of alcohol reduction remain unclear. We evaluated the long-term associations of sustained alcohol reduction with glycemic, blood pressure, and lipid profiles. MATERIALS AND METHODS:We conducted a pooled sequential target trial emulation using annual health examination data from Japanese employees (2008-2023). Eligible participants were aged ≥ 40 years and consumed ≥ 20 g/day of ethanol at baseline. Participants subsequently reducing alcohol intake to < 20 g/day formed the intervention group; those maintaining ≥ 20 g/day formed the control group. We applied inverse probability weighting to estimate the per-protocol effect of sustained alcohol reduction. We used weighted generalized estimating equations to estimate longitudinal trajectories of fasting plasma glucose (FPG), systolic blood pressure (SBP), diastolic blood pressure (DBP), triglycerides, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. RESULTS:Among 266 699 eligible trial entries, 30 280 and 229 946 trial entries were included in the intervention and control groups, respectively. Alcohol reduction was associated with persistently lower FPG, SBP, DBP, and triglycerides over 15 years. At Year 15, between-group differences were -1.8 mg/dL for FPG, -3.4 mmHg for SBP, -2.2 mmHg for DBP and -20.4 mg/dL for triglycerides (all p ≤ 0.005). Conversely, HDL cholesterol levels were consistently lower and LDL cholesterol levels modestly higher in the intervention group. Blood pressure-lowering effects were consistent across genders, and findings were broadly consistent across sensitivity, subgroup, and dose-transition analyses. CONCLUSIONS:Sustained alcohol reduction improved long-term FPG, blood pressure, and triglycerides. These findings support alcohol reduction as a potentially beneficial lifestyle intervention for improving cardiometabolic profiles.
OBJECTIVE:To evaluate dose-normalised time in range (dn-TIR) and its log relative change (Δdn-TIR) as measures of within-person glycaemic change relative to total daily insulin exposure following hybrid closed-loop therapy (HCL/AID). RESEARCH DESIGN AND METHODS:We conducted a retrospective two-cohort study of people with type 1 diabetes commencing hybrid closed-loop/automated insulin delivery (HCL/AID) therapy in Australia and the United Kingdom (UK). dn-TIR was calculated as time in range (TIR) 3.9-10.0 mmol/L (70-180 mg/dL) divided by total daily insulin dose (TDD) and Δdn-TIR as log[(TIR/TDD)post/(TIR/TDD)pre]. RESULTS:The study comprised 86 people living with type 1 diabetes in Australia and 288 in the UK. In the fixed Australian dn-TIR cohort, TIR increased from 53.2% ± 20.7% to 70.4% ± 14.6% (n = 86; p < 0.001), whereas mean TDD changed from 53.3 to 52.0 units/day (n = 86; p = 0.724). Median Δdn-TIR was 0.224 [IQR: -0.033, 0.583]. In the UK cohort, TIR increased from a median 54% [34, 68] to 66% [54, 74] (n = 257; p < 0.001), whereas mean TDD changed from 44.1 to 46.3 units/day (n = 242; p = 0.152). Median Δdn-TIR was 0.194 [IQR: -0.097, 0.541]. CONCLUSIONS:HCL/AID therapy improved TIR relative to TDD in two real-world cohorts. dn-TIR and Δdn-TIR are not replacements for established CGM metrics or direct measures of insulin sensitivity; they may provide an adjunct longitudinal description of whether glycaemic improvement was accompanied by proportionately greater, similar or lower insulin exposure.
BACKGROUND:Low-density lipoprotein cholesterol (LDL-C) goal attainment is central to primary atherosclerotic cardiovascular disease (ASCVD) prevention, but LDL-C may not fully reflect the burden of apolipoprotein B (ApoB)-containing atherogenic particles. The prevalence and clinical correlates of residual ApoB elevation among adults who have attained PREVENT risk-stratified LDL-C goals remain unclear. METHODS:This cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) 2005-2016 from adults aged 30-79 years without known ASCVD. The primary analytic sample included participants with 10-year PREVENT-ASCVD risk ≥ 3% who attained risk-stratified LDL-C goals. Residual ApoB elevation was defined as ApoB ≥ 90 mg/dL for PREVENT-ASCVD risk 3% to < 10% and ≥ 70 mg/dL for risk ≥ 10%. Survey-weighted analyses were used to estimate prevalence and identify factors associated with residual ApoB elevation. RESULTS:Among 3857 adults with PREVENT-ASCVD risk ≥ 3%, 908 (23.5%) attained risk-stratified LDL-C goals. Of these, 128 had residual ApoB elevation, corresponding to a weighted prevalence of 17.7% (95% CI, 14.5%-21.4%). The prevalence was substantially higher among participants with triglycerides 150-400 mg/dL than among those with triglycerides < 150 mg/dL (43.6% vs. 4.3%; p < 0.001). In multivariable logistic regression, triglycerides of 150-400 mg/dL were strongly associated with residual ApoB elevation (adjusted OR, 15.87; 95% CI, 8.28-30.41; p < 0.001). Higher odds were also observed for PREVENT-ASCVD risk ≥ 10%, obesity, metabolic syndrome and advanced cardiovascular-kidney-metabolic stages (CKM Stages 2-4). The association with triglycerides was consistent across exploratory subgroups and robust in sensitivity analyses. CONCLUSIONS:Among U.S. adults without known ASCVD who attained PREVENT risk-stratified LDL-C goals, residual ApoB elevation was common and strongly associated with triglyceride elevation. The prognostic and clinical significance of this discordant phenotype remains to be established.
AIMS:To evaluate whether intravitreal ranibizumab (IVR) frequency is associated with longitudinal renal markers in diabetic macular oedema (DMO) and whether the expected systemic renal and haematological effects of SGLT2 inhibition are reproduced. MATERIALS AND METHODS:In this post hoc sub-analysis of the prospective COMET randomised controlled trial, 53 participants were analysed. The estimated glomerular filtration rate (eGFR), haematocrit (Hct), and urinary albumin-to-creatinine ratio (UACR) were assessed over 48 weeks using linear mixed-effects models with the treatment group, week, group-by-week interaction, and cumulative IVR as fixed effects. RESULTS:Baseline eGFR was preserved (72.2 ± 18.5 mL/min/1.73 m2) despite common albuminuria (median UACR 50.6 mg/gCr); mean cumulative IVR at week 48 was 7.00 ± 4.42. Cumulative IVR was not significantly associated with eGFR (-0.22 mL/min/1.73 m2 per injection; 95% CI -0.59 to 0.15; p = 0.25), ln(UACR), or Hct. The SGLT2 inhibitor reproduced an early eGFR dip and Hct rise. CONCLUSIONS:No statistically significant exposure-response association was detected between cumulative IVR and renal markers within the COMET trial cohort and dosing range. Because all participants received IVR and the sample size was modest, small cumulative renal effects cannot be excluded. TRIAL REGISTRATION:University Hospital Medical Information Network Center (UMIN000057674); Japan Registry of Clinical Trials (jRCTs031180210, parent COMET trial).
BACKGROUND:Antenatal corticosteroids (ACS) promote foetal lung maturation in pregnancies at risk of preterm birth; however, in gestational diabetes mellitus (GDM), they can exacerbate maternal glycemia and contribute to adverse neonatal outcomes. Clinical guidelines offer limited direction on optimal treatment adjustment. OBJECTIVES:To synthesize the evidence on glycaemic responses and management strategies following ACS exposure in individuals with GDM. METHODS:A systematic review of Embase, MEDLINE and CENTRAL in October 2025 in accordance with PRISMA guidelines. Studies reporting on glycaemic outcomes and/or management strategies following ACS exposure in individuals with GDM were included. RESULTS:Twenty studies were included. Maternal glycemia rose predictably after ACS, with hyperglycaemia typically emerging within 9-16 h, peaking over the subsequent 24-72 h and often persisting up to 5 days. Among individuals managed with medical nutrition therapy or oral hypoglycaemic agents at baseline, insulin initiation ranged from 13% to 91%. Among those already using insulin, 67%-88% required dose escalation, with mean increases typically ranging from 47% to 91%. Pregnancy-adapted intravenous insulin (IVI) pathways reported higher time-in-range and fewer hyperglycaemic/hypoglycaemic events than adult IVI protocols. However, emerging evidence suggests that structured, pregnancy-specific subcutaneous insulin protocols may achieve comparable or improved glycaemic control. CONCLUSIONS:ACS exposure in GDM is associated with a predictable but variable, transient deterioration in maternal glycaemia. GDM-specific evidence suggests that structured pregnancy-adapted monitoring and insulin-adjustment pathways may help attenuate post-ACS hyperglycaemia. However, the evidence remains heterogeneous and largely observational. Prospective studies are needed to validate GDM-specific algorithms, clarify thresholds for insulin initiation or escalation and define indications for subcutaneous versus IVI.
AIMS:No studies have investigated the synergistic effectiveness of Glucagon-Like Peptide 1 Receptor Agonists (GLP1RAs) in patients with persistent obesity following bariatric surgery. The GLP-1 Receptor Agonists Post-Bariatric Surgery (GRABS) Trial aims to investigate the effectiveness of tirzepatide (TRZ) versus standard of care (SOC) after Roux-en-Y gastric bypass (RYGB) in patients with persistent obesity (body mass index [BMI] ≥ 30 kg/m2). MATERIALS AND METHODS:This randomized, open-label proof-of-concept trial compares 24 weeks of TRZ with SOC versus SOC alone after RYGB. The primary outcome is total percent weight change from baseline to 24 weeks after trial initiation. Patients aged 25-65 with BMI ≥ 30 kg/m2 enroled 12 months after RYGB are randomized 1:1 to 24 weeks of TRZ or SOC. Exclusion criteria include: type 1 diabetes, type 2 diabetes treatment other than metformin, conversion to RYGB from prior bariatric surgery, and GLP1RA use in the past 3 months. RESULTS:The study enroled 33 patients, with 5 withdrawals prior to completing a baseline visit, resulting in a final sample of 28 patients. The final cohort is 82% female, 75% white, median age 42.0 years, pre-surgery BMI of 48.3 kg/m2, baseline BMI at randomization of 36.0 kg/m2 and baseline weight of 95.6 kg. CONCLUSIONS:GRABS is the first randomized trial to investigate GLP1RA effectiveness in patients with persistent obesity following RYGB, with the potential to inform synergistic adjuvant strategies to enhance surgical weight loss. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT06162715.
BACKGROUND AND AIM:Fabry disease (FD) is frequently complicated by renal impairment and cardiovascular events; however, evidence on sodium-glucose cotransporter-2 inhibitors (SGLT2i) in this population is scarce. Accordingly, we assessed the association between SGLT2i exposure and cardiovascular outcomes in adults with FD. METHODS:We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, including adults with Fabry disease and eGFR ≥ 20 mL/min/1.73 m2, excluding Type 1 diabetes. Patients were stratified by SGLT2 inhibitor exposure. The primary outcome was a composite of all-cause death, acute myocardial infarction and acute or acute-on-chronic heart failure at 2 and 5 years; secondary outcomes included individual components and progression to advanced kidney disease. Patients with prior non-fatal outcomes were excluded from the respective analyses. Propensity score matching (1:1) and Cox proportional hazards models were used. Sensitivity analyses included alternative follow-up periods, restriction to Fabry disease diagnosed from 2013 onwards and a stricter Fabry disease definition requiring ≥ 2 diagnoses; subgroup analyses were performed by sex and age. RESULTS:Among 14 940 FD patients, 1028 (6.9%) had recorded exposure to SGLT2 inhibitors (mean age: 65.5 ± 12.0 years; 53.0% male), who were older and had a higher comorbidity burden and worse baseline renal profile than non-exposed patients. After PSM, 732 patients per group (exposed and non-exposed patients) were available for analysis. At 2 years, SGLT2i exposure was associated with a lower risk of the composite outcome (HR 0.61; 95% CI 0.38-0.97) and all-cause death (HR 0.56; 95% CI 0.33-0.95). At 5 years, results were consistent for the composite outcome (HR 0.56; 95% CI 0.39-0.79) and all-cause death (HR 0.62; 95% CI 0.42-0.93), with reduced myocardial infarction risk (HR 0.53; 95% CI 0.30-0.90). CONCLUSIONS:In a large real-world FD cohort, SGLT2i exposure was associated with lower cardiovascular risk and mortality, supporting further prospective investigation.
AIMS:To compare cardiovascular, kidney, and liver outcomes of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus seven other antidiabetic medications (ADMs) in Chinese patients with Type 2 diabetes. MATERIALS AND METHODS:This retrospective cohort study (2018-2024) used an Eastern China regional healthcare database. We included patients initiating GLP-1 RAs, sodium-glucose cotransporter-2 inhibitors (SGLT-2 inhibitors), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), insulins, sulfonylureas, α-glucosidase inhibitors (AGIs), thiazolidinediones, or meglitinides. Outcomes were major adverse cardiovascular (MACE), kidney (MAKE), and liver (MALO) events. A propensity score-based matching weights (MWs) approach was used to balance covariates including demographics, comorbidities, and medication use, and Cox proportional hazards models were conducted in both intention-to-treat and per-protocol analyses. RESULTS:Among 105 391 patients, SGLT-2 inhibitors (HR 1.19, 95% CI 1.10-1.30), insulins (HR 1.42, 95% CI 1.32-1.52), sulfonylureas (HR 1.30, 95% CI 1.18-1.43), and AGIs (HR 1.45, 95% CI 1.31-1.59) were associated with higher MACE risk compared with GLP-1 RAs. DPP-4 inhibitors (HR 3.09, 95% CI 1.69-5.63), insulins (HR 6.11, 95% CI 4.37-8.54), and meglitinides (HR 4.56, 95% CI 2.32-8.97) were associated with higher MAKE risk. Higher MALO risk was observed with DPP-4 inhibitors (HR 1.48, 95% CI 1.21-1.79), insulins (HR 2.06, 95% CI 1.81-2.34), AGIs (HR 1.55, 95% CI 1.26-1.90), and meglitinides (HR 1.43, 95% CI 1.07-1.92). CONCLUSIONS:GLP-1 RAs were associated with favourable cardio-renal-metabolic outcomes compared with several second-line glucose-lowering agents, particularly insulins and sulfonylureas. These findings add to the real-world evidence supporting the potential cardiovascular, renal, and hepatic benefits of GLP-1 RAs in patients with T2DM.
AIMS:Type 2 diabetes (T2D) is a heterogeneous disorder with substantial variation in age at onset (AAO). This study aimed to characterize the distinct genetic architectures and biological mechanisms underlying extreme AAO-defined T2D subtypes. MATERIALS AND METHODS:Using 74 795 European-ancestry participants from the UK Biobank, we performed genome-wide association studies (GWAS) of relatively early-onset T2D (eoT2D; AAO < 55 years) and late-onset T2D (loT2D; AAO ≥ 70 years). We investigated subtype-specific genetic loci, SNP-based heritability, genetic correlations, Mendelian randomization (MR)-based relationships, polygenic risk scores (PRS) and phenome-wide association studies (PheWAS). Single-cell transcriptomic data from human pancreatic tissues were further used to evaluate cell-type-specific expression patterns of candidate genes. RESULTS:SNP-based heritability was substantially higher for eoT2D than loT2D (11.2% vs. 6.4%), with eoT2D displaying distinct genetic loci related to β-cell function and insulin regulation, including SLC30A8 and IRS1. By contrast, loT2D showed a comparatively lipid-related genetic profile, featuring APOE-associated signals and expression patterns in immune-related cell populations. Linkage disequilibrium score regression (LDSC) and MR analyses further underscored this divergence: eoT2D exhibited broader genetic overlap with cardiometabolic traits, whereas loT2D showed stronger relationships with traditional metabolic risk factors. Finally, subtype-specific PRSs improved risk discrimination beyond conventional covariates, although their clinical utility warrants further evaluation. CONCLUSIONS:Extreme AAO-defined T2D subtypes exhibit partially distinct genetic architectures, highlighting AAO as an important dimension of T2D heterogeneity and providing a framework for future age-stratified genetic risk assessment.
AIMS:To investigate the association between baseline metformin use and incident hearing loss among participants with diabetes in the UK Biobank. MATERIALS AND METHODS:This study included participants from the UK Biobank who had been diagnosed with diabetes before baseline and had no evidence of hearing loss (N = 24 981). Metformin use was determined based on self-reported medication use at the baseline assessment. Incident hearing loss was ascertained using a composite definition based on speech-reception-threshold estimate, hearing aid use, cochlear implantation and relevant ICD-10 diagnoses during follow-up. Cox proportional hazards models were used, with analyses stratified by sex and adjusted for demographic, lifestyle, socioeconomic, clinical factors, noise exposure, use of antidiabetic medications and renal function. RESULTS:During approximately 12 years of follow-up, 725 and 385 incident hearing loss events were observed among male and female participants, respectively. Sex-stratified analyses showed that, among men with diabetes, baseline metformin use was associated with a lower risk of incident hearing loss (fully adjusted model: hazard ratio [95% confidence interval], 0.846 [0.725-0.987], p = 0.0339), and this association remained generally stable across multiple sensitivity analyses. In contrast, among women with diabetes, no statistically significant association was observed between metformin use and the risk of incident hearing loss (fully adjusted model: hazard ratio [95% confidence interval], 0.977 [0.790-1.208], p = 0.8290). Further interaction analysis showed that the interaction term between metformin use and sex was not statistically significant (p for interaction = 0.260). CONCLUSIONS:In participants with diabetes from the UK Biobank, baseline metformin use was associated with a lower risk of incident hearing loss among men, whereas no significant association was observed among women. However, the interaction term between metformin use and sex was not statistically significant; therefore, it cannot yet be concluded that this association differed by sex.
AIM:To develop a next-generation, longer-acting, more-clinical-benefits agonist to achieve sustained efficacy with improved tolerability. METHODS:CT130 was designed from semaglutide. Binding affinity was validated via molecular dynamics and cellular assays. Pharmacokinetics were profiled in SD rats; metabolic efficacy was evaluated in B6/ob and DIO mice (CT130 biweekly vs semaglutide weekly). Receptor trafficking dynamics and cholesterol regulation were dissected mechanistically. Toxicology was assessed in rodents and a primate pilot study. RESULTS:CT130 retained high GLP‑1R affinity (EC50 = 21 pM) and exhibited a prolonged half‑life (13.9 h, 1.4‑fold vs semaglutide). Biweekly CT130 outperformed weekly semaglutide in body weight reduction, glucose tolerance, TC, LDL‑C, body fat percentage and other metabolic indicators. Drug‑free intervals enabled near‑complete GLP‑1R recycling, termed "GLP‑1R recovery", preserving receptor homeostasis, whereas semaglutide drove progressive internalization. CT130 also alleviated constipation risk (increased fecal water) and uniquely lowered cholesterol by suppressing SREBP‑2, which upregulated LDLR while decoupling from PCSK9 induction, thereby promoting fecal cholesterol excretion without altering bile acid flux. No pathological changes were observed even at tens to 200 times the semaglutide dose. In monkeys, two biweekly doses induced > 10% weight loss with good safety. CONCLUSIONS:CT130 is a safe, once biweekly preclinical candidate that incorporates drug free intervals to allow GLP 1R restore. It delivers robust, lasting metabolic benefits with improved gastrointestinal tolerability, and offering a template for next generation long acting GLP 1R agonists.
AIMS:To estimate the prevalence and incidence of hypoglycaemia and the variations in Chinese type 2 diabetes (T2D) patients. MATERIALS AND METHODS:A multi-centre, non-interventional study was conducted across 103 hospitals in 20 provinces in China between 18 March 2022 and 5 December 2023. The study adopted an integrated 12-week prospective cohort study design, enrolling 15 437 adults with T2D. Hypoglycaemic events were captured through a structured questionnaire and patient diary, including laboratory-confirmed, symptomatic, any, severe and nocturnal hypoglycaemia. Variations in hypoglycaemia burden were examined by socio-demographic factors, health status, treatment regimens, geographic region and hospital level. The endpoints were the prevalence of patients experiencing at least one hypoglycaemic event and the corresponding incidence during the study period. RESULTS:The 15 437 participants who completed the follow-up at Week 12 were included in this study. During this period, 9.0% [95% CI: 8.6, 9.5] of the participants experienced at least one hypoglycaemic event, corresponding to an incidence rate of 79.8 [76.9, 82.8] events per 100 person-years. Hypoglycaemia burden differed markedly according to treatment background. The 12-week prevalence of any hypoglycaemia was 5.5%, 9.7% and 12.2% among participants receiving neither insulin nor secretagogues, secretagogues without insulin and insulin, respectively, with corresponding incidence rates of 48.6, 105.0 and 104.3 events per 100 person-years. Similar treatment-related patterns were observed for laboratory-confirmed, symptomatic and nocturnal hypoglycaemia. Hypoglycaemia burden also varied substantially across age, diabetes duration, body mass index (BMI), HbA1c, geographic region and hospital level. Greater hypoglycaemia burden was generally observed among participants with longer diabetes duration and lower BMI. The prevalence of any hypoglycaemia was highest in the eastern region and tertiary hospitals, whereas its incidence rate was highest in western regions and primary hospitals. CONCLUSIONS:Although the prevalence and incidence of hypoglycaemia among Chinese T2D patients were lower than previous studies, hypoglycaemia still remains a significant clinical concern. These findings highlight the importance of individualized strategies for glycaemic management to minimize hypoglycaemia risk in routine diabetes care. TRIAL REGISTRATION:Chinese Clinical Trial Registry: ChiCTR2100053847.
